Zhang Ying, Lu Weiqing, Chen Yelong, Lin Youbin, Yang Xia, Wang Hu, Liu Zhaoyong
Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Mol Oncol. 2021 May;15(5):1566-1583. doi: 10.1002/1878-0261.12934. Epub 2021 Mar 14.
Esophageal squamous cell carcinoma (ESCC) is one of the most refractory malignancies worldwide. Mitogen-activated protein kinase 3 (MAP2K3) has a contradictory role in tumor progression, and the function and expression patterns of MAP2K3 in ESCC remain to be determined. We found that MAP2K3 expression to be downregulated in ESCC, and MAP2K3 downregulation correlated with clinically poor survival. MAP2K3 inhibited ESCC cell proliferation and invasion in vitro and in vivo. MAP2K3 suppressed STAT3 expression and activation. Mechanistically, MAPSK3 interacted with MDM2 to promote STAT3 degradation via the ubiquitin-proteasome pathway. Furthermore, exosomal miR-19b-3p derived from the plasma of patients with ESCC could suppress MAP2K3 expression to promote ESCC tumorigenesis. STAT3 was found to bind to the MIR19B promoter and increased the expression of miR-19b-3p in ESCC cells. In summary, our results demonstrated that the miR-19b-3p-MAP2K3-STAT3 feedback loop regulates ESCC tumorigenesis and elucidates the potential of therapeutically targeting this pathway in ESCC.
食管鳞状细胞癌（ESCC）是全球最难治的恶性肿瘤之一。丝裂原活化蛋白激酶3（MAP2K3）在肿瘤进展中具有矛盾的作用，其在ESCC中的功能和表达模式仍有待确定。我们发现MAP2K3在ESCC中表达下调，且MAP2K3下调与临床预后不良相关。MAP2K3在体外和体内均抑制ESCC细胞增殖和侵袭。MAP2K3抑制STAT3表达和激活。机制上，MAPSK3与MDM2相互作用，通过泛素-蛋白酶体途径促进STAT3降解。此外，源自ESCC患者血浆的外泌体miR-19b-3p可抑制MAP2K3表达以促进ESCC肿瘤发生。发现STAT3与MIR19B启动子结合并增加ESCC细胞中miR-19b-3p的表达。总之，我们的结果表明miR-19b-3p-MAP2K3-STAT3反馈环调节ESCC肿瘤发生，并阐明了靶向该途径治疗ESCC的潜力。
